CN102153559A - Novel method for synthesizing sitagliptin phosphate and derivatives thereof - Google Patents
Novel method for synthesizing sitagliptin phosphate and derivatives thereof Download PDFInfo
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- 229960004115 sitagliptin phosphate Drugs 0.000 title claims abstract description 41
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 39
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 104
- 239000002994 raw material Substances 0.000 claims abstract description 40
- 229960005261 aspartic acid Drugs 0.000 claims abstract description 33
- 230000009467 reduction Effects 0.000 claims abstract description 26
- 230000007062 hydrolysis Effects 0.000 claims abstract description 23
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 23
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims abstract description 20
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims abstract description 20
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 20
- 230000032050 esterification Effects 0.000 claims abstract description 18
- 238000005886 esterification reaction Methods 0.000 claims abstract description 18
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 15
- 230000008878 coupling Effects 0.000 claims abstract description 13
- 238000010168 coupling process Methods 0.000 claims abstract description 13
- 238000005859 coupling reaction Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 62
- 238000001035 drying Methods 0.000 claims description 50
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 239000007787 solid Substances 0.000 claims description 40
- 239000007788 liquid Substances 0.000 claims description 38
- 238000000967 suction filtration Methods 0.000 claims description 38
- 238000003756 stirring Methods 0.000 claims description 37
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 claims description 35
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 claims description 35
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 239000012452 mother liquor Substances 0.000 claims description 30
- 229910052740 iodine Inorganic materials 0.000 claims description 29
- 239000011630 iodine Chemical group 0.000 claims description 29
- 238000005406 washing Methods 0.000 claims description 28
- 125000002346 iodo group Chemical group I* 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- 125000003368 amide group Chemical group 0.000 claims description 20
- 230000002633 protecting effect Effects 0.000 claims description 20
- 238000000605 extraction Methods 0.000 claims description 18
- -1 methoxyl group Chemical group 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 16
- 239000013078 crystal Substances 0.000 claims description 16
- 239000006260 foam Substances 0.000 claims description 16
- 238000003760 magnetic stirring Methods 0.000 claims description 16
- 238000006386 neutralization reaction Methods 0.000 claims description 16
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 229960004034 sitagliptin Drugs 0.000 claims description 15
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 14
- 239000007791 liquid phase Substances 0.000 claims description 14
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- UPCKPWDYXMTASO-UHFFFAOYSA-N 1,2,4-trifluoro-5-iodobenzene Chemical compound FC1=CC(F)=C(I)C=C1F UPCKPWDYXMTASO-UHFFFAOYSA-N 0.000 claims description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 238000013019 agitation Methods 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 150000002460 imidazoles Chemical class 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 238000010025 steaming Methods 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 239000000052 vinegar Substances 0.000 claims description 8
- 235000021419 vinegar Nutrition 0.000 claims description 8
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 7
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- OWQUYBAASOSGNO-CDNKMLFNSA-N 2-[[(Z)-N-(2-hydroxy-5-sulfoanilino)-C-phenylcarbonimidoyl]diazenyl]benzoic acid Chemical compound C1=CC=C(C=C1)/C(=N/NC2=C(C=CC(=C2)S(=O)(=O)O)O)/N=NC3=CC=CC=C3C(=O)O OWQUYBAASOSGNO-CDNKMLFNSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 229940043798 zincon Drugs 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 5
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 claims description 4
- 230000008034 disappearance Effects 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 3
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- NUESBWDCFNLGSQ-COBSHVIPSA-N CC([C@@H](CO)NC(=O)OC(C)(C)C)C(=O)O Chemical compound CC([C@@H](CO)NC(=O)OC(C)(C)C)C(=O)O NUESBWDCFNLGSQ-COBSHVIPSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 229940125773 compound 10 Drugs 0.000 claims 1
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 claims 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 3
- 238000010640 amide synthesis reaction Methods 0.000 abstract 1
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- 230000026045 iodination Effects 0.000 abstract 1
- 238000006192 iodination reaction Methods 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 230000004224 protection Effects 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel method for synthesizing sitagliptin phosphate and derivatives thereof. The method has the advantages of easily obtained raw materials, mild reaction conditions, no need of using a particularly expensive catalyst, easily controlled optical purity and the like. The invention relates to a novel method for synthesizing sitagliptin phosphate and a derivative thereof, which takes L-aspartic acid as a raw material, and obtains sitagliptin phosphate chiral salt and a hydrate thereof through the steps of amino protection, esterification, reduction, iodination or bromination, coupling, hydrolysis, amide formation, deprotection group and salt formation chemical reaction.
Description
Technical field
The present invention relates to a kind of method of synthetic drugs intermediate, more specifically to the novel method of a kind of synthetic sitagliptin phosphate and derivative thereof.
Background technology
Sitagliptin phosphate (sitagliptin) is the 1st dipeptidyl peptidase-IV (DPP-IV) inhibitor of FDA approval listing, is used for the treatment of diabetes B, and its structural formula is as follows:
(3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) butyric acid or its methyl esters, ethyl ester are the key intermediates of sitagliptin phosphate.People such as Kim have delivered the first-generation synthetic route [J.Med.Chem.2005,48 (1): 141.] of sitagliptin, and this method induces chiral by chiral raw material, and back diazotization reaction produces beta-amino acids and constructs chiral centre.This method has significant limitation, and its reaction was both loaded down with trivial details, and product is confined on the gram magnitude of research department.Its step is as follows:
Merck company has delivered in two pieces of patents of 2004 (W02004085378) and 2005 (WO2005020920) with the chirality rhodium catalyst enamine has been carried out the novel method that asymmetric hydrogenation is constructed the synthetic sitagliptin of chiral centre.Though compared with original out-of-date methods, significantly reduced the production cost of sitagliptin, cost is very expensive.
Human chiral phosphorus root ruthenium catalysts such as Hansen carry out asymmetric hydrogenation to ketone and construct chiral secondary alcohol, after secondary alcohol is converted into secondary amine method synthesized sitagliptin [Org.Proc.Res.Dev.2005,9 (5), 634].Compared with Merck company, though this method has been simplified reactions steps, the ee value has had large increase, and cost is still expensive.Its step is as follows:
The people such as Jin Hee Ahn of Korea S in 2007 have invented another kind of method, but the ee value is difficult to improve.Concrete steps are as follows:
In order to solve deficiency and the problem that above-mentioned prior art exists, need a kind of mild condition of exploitation, the synthetic sitagliptin phosphate that raw material is easy to get and the novel method of derivative thereof are to satisfy the market requirement that increases day by day.
Summary of the invention
The invention solves above-mentioned the deficiencies in the prior art and problem, the novel method of a kind of synthetic sitagliptin phosphate and derivative thereof is provided.This method has that raw material is easy to get, the reaction conditions temperature, do not use advantages such as valuable especially catalyzer and optical purity be easy to control.
The present invention is achieved by the following technical solutions:
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof, it is to be raw material with the L-aspartic acid, through amido protecting, esterification, reduction, iodo or bromo, coupling, hydrolysis and amidated and deprotection base and salify chemical reaction step obtain sitagliptin phosphate chirality salt and hydrate thereof, be raw material at first with the L-aspartic acid, through amido protecting, esterification, reduction and iodo obtain as compound in structural formula I A, compd A obtains Compound C as structural formula II I through linked reaction again with as the compd B of structural formula II, and Compound C is passed through hydrolysis and amidated again, deprotection base and salt-forming reaction prepare the sitagliptin phosphate hydrate; Compd A, B, C-structure formula are as follows:
Wherein:
R
1, R
2Be H atom or amino protecting group tertbutyloxycarbonyl, benzyl, carbobenzoxy, phthaloyl;
R
3For methoxyl group, oxyethyl group, tert.-butoxy, benzyloxy or as the group of structural formula IV;
X is bromine, iodine or zincon, boric acid;
Y is triflate, methanesulfonates, p-methyl benzenesulfonic acid ester, bromine or iodine or its zincon;
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof, its further technical scheme are that described linked reaction is to obtain Compound C by reaction with chemical combination B under catalyst action again after compd A and magnesium or n-Butyl Lithium or the lithium reaction; Perhaps described linked reaction is that reaction obtains Compound C to compd A formation zincon with compd B again; Further technical scheme is that described catalyzer is bi triphenyl phosphorus Palladous chloride, palladium chloride, nickelous chloride, two (dibenzalacetone) palladium, tetra-triphenylphosphine palladium or palladium again; Further technical scheme can also be that described linked reaction may further comprise the steps again: get zinc powder and DMF, 50 ℃ of N
2Protection adds glycol dibromide, stirring reaction 20min down, stop heating, add trimethylchlorosilane down, react faint heat release at 30 ℃, add compound in structural formula I A and the DMF solution that obtains through iodo behind the 20min, the some plate is followed the tracks of reaction, and raw material point disappears behind the 30min, add catalyzer, 30 ℃ of following syringes slowly inject 2,4,5-trifluoro iodobenzene or 2,4, the 5-trifluorobromobenzene, exothermic heat of reaction, adding finishes, high performance liquid phase is followed the tracks of reaction, raw material point is used the ethyl acetate dilute reaction solution after disappearing, suction filtration, mother liquor saturated common salt water washing and washing, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product; Perhaps described linked reaction may further comprise the steps: get the zinc-copper mixture, will be added to through the compound in structural formula I A that iodo obtains among benzene and the DMF, 50 degree N
2Protection adds catalyzer and 2,4,5-trifluoro iodobenzene or 2 down, 4, the 5-trifluorobromobenzene is in 70 degree reaction 15h, adding finishes, and high performance liquid phase is followed the tracks of reaction, ethyl acetate dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times is washed 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product; Perhaps described linked reaction may further comprise the steps: in exsiccant 20ml ether, add magnesium, add 2,4 again, 5-trifluoro iodobenzene 2.1g or 2.3g 2,4,5-trifluorobromobenzene, N
2Protection adds a small amount of iodine down and causes stirring reaction 20min, and 50 degree add the dimethyl sulfide cuprous bromide after 1 hour again; stirring at room 1h, cooling adds the compound in structural formula I A that iodo obtains, and high performance liquid phase is followed the tracks of reaction; after raw material point disappears; ethyl acetate 50ml dilute reaction solution, suction filtration, mother liquor; saturated common salt water washing 2 times; wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product.
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof, its further technical scheme can also be that described amido protecting may further comprise the steps: magnetic stirring apparatus is being housed, add L-aspartic acid 20g in the there-necked flask of thermometer, methyl alcohol 200ml, cooling Dropwise 5 ml sulfur oxychloride, drip stirring at room 5h, the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid methyl ester hydrochloride 40g; Magnetic stirring apparatus is being housed, add L-aspartic acid and sodium bicarbonate in the there-necked flask of thermometer, water-soluble and 1, in the 4-dioxane, molten clear back adds the BOC acid anhydrides, stirring is spent the night, suction filtration, mother liquor adds water, regulates pH with hydrochloric acid, through after extraction, the drying, the concentrating under reduced pressure desolventizing obtains the pale yellow oily liquid body again.
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof; its further technical scheme can also be that described esterification may further comprise the steps: the pale yellow oily liquid body that amido protecting is obtained is dissolved in the ethyl acetate; add N-maloyl imines again, agitation and dropping EDCI is dissolved in ethyl acetate; stir; suction filtration, mother liquor washed twice, organic phase anhydrous sodium sulfate drying; the concentrating under reduced pressure desolventizing gets the pale yellow oily liquid body.
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof, its further technical scheme can also be that described reduction may further comprise the steps: get sodium borohydride and be dissolved in THF, be added drop-wise in pale yellow oily liquid body and THF that esterification obtains, when having a large amount of bubbles to generate, temperature is increased to 30 degree, drip and finish, the point plate reacts completely ethyl acetate extraction, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets the pale yellow oily liquid body; Described iodo may further comprise the steps: triphenyl phosphorus is dissolved in methylene dichloride, molten clear back adds imidazoles and iodine, temperature rises to 34 ℃, drip the pale yellow oily liquid body that obtains through reduction and the solution of 20ml methylene dichloride behind the reaction 20min, the some plate is followed the tracks of reaction, suction filtration after raw material point disappears, the saturated common salt washing, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid.
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof, its further technical scheme can also be that described hydrolysis and amidated may further comprise the steps: the product adding methyl alcohol and the mass percent that will obtain through coupling are 30% lithium hydroxide aqueous solution, after reacting completely, the neutralization extraction, add DCC after dry the concentrating, 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and triethylamine slowly rises to and continues the reaction after-filtration that finishes after the room temperature and remove the N of generation, a N ' dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again to revolve less to steam to remove after residue dissolves with small amount of acetic acid second vinegar and desolvate, the residue column chromatography for separation gets white foam shape solid.
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof; its further technical scheme can also be that described deprotection base and salify may further comprise the steps: the white foam shape solid that hydrolysis and amidated are obtained is dissolved in the methylene dichloride; add trifluoroacetic acid; react after 3 hours; pour in the frozen water; neutralization, extraction concentrates the back and adds ethanol; after adding massfraction 85% phosphate aqueous solution again; temperature rises to 70～74 ℃, adds the sitagliptin phosphate crystal seed, at room temperature places 18h; filter crystal; wash with ethanol, 40 ℃ of following vacuum-dryings promptly get white powder solid phosphoric acid sitagliptin hydrate.
The novel method of synthetic sitagliptin phosphate of the present invention and derivative thereof; its further technical scheme can also be described be raw material with the L-aspartic acid; process amido protecting, esterification, reduction, iodo, coupling, hydrolysis and amidated and deprotection base and salify chemical reaction step obtain sitagliptin phosphate chirality salt and hydrate thereof, and it specifically may further comprise the steps:
1) amido protecting
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, methyl alcohol 200ml, cooling Dropwise 5 ml sulfur oxychloride drips stirring at room 5h, and the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid methyl ester hydrochloride 40g; Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, yellow soda ash 20g, water-soluble and 1, in the 4-dioxane, molten clear back adding BOC acid anhydrides, stirring is spent the night, and suction filtration, mother liquor add water 2L, regulate pH with hydrochloric acid.Use ethyl acetate extraction then 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing obtain pale yellow oily liquid body N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters 31g;
2) esterification
30g N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters is dissolved in the ethyl acetate, add N-maloyl imines 29g again, agitation and dropping 30g EDCI, be dissolved in the 100ml ethyl acetate, stir suction filtration, the mother liquor washed twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets pale yellow oily liquid body (3S)-N-tertbutyloxycarbonyl-3-amino-4-succimide oxygen base methyl-butyrate 39g; The 30g pale yellow oily liquid body that amido protecting is obtained is dissolved in the methylene dichloride, and cooling adds the 45g isobutyl chlorocarbonate, adds 23gN-maloyl imines again, be stirred to fully, add water washing twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets the pale yellow oily liquid body;
3) reduction and iodo
Reduction: get the 1.4g sodium borohydride and be dissolved in 100mlTHF, be added drop-wise to 20g in pale yellow oily liquid body and 50mlTHF that esterification obtains, there are a large amount of bubbles to generate, temperature is increased to 30 ℃, drips to finish the some plate, react completely, ethyl acetate extraction 2 times, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets 5.5g;
Iodo: the 9.8g triphenyl phosphorus is dissolved in the 70ml methylene dichloride, molten clear back adds the 1g imidazoles, adds 2g iodine, and it is 34 Celsius that temperature rises to, behind the reaction 20min, slowly add the pale yellow oily liquid body that above-mentioned reduction obtains, the some plate is followed the tracks of reaction, suction filtration after raw material point disappears, saturated common salt washing 2 times, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate 3.5g;
4) coupling
Get zinc powder 1.48g, 2.5mlDMF, 50 degree N
2Protection adds glycol dibromide 1ml, stirring reaction 20min down, stop heating, 30 degree add trimethylchlorosilane down, react faint heat release, add 1.3g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate and 10mlDMF solution behind the 20min, the some plate is followed the tracks of reaction, and raw material point disappears behind the 30min, add catalyzer 0.2g, 30 degree syringe down slowly inject 2,4,5-trifluoro iodobenzene 1.27g or 1.20g 2,4, the 5-trifluorobromobenzene, exothermic heat of reaction, adding finishes, high performance liquid phase is followed the tracks of reaction, ethyl acetate 50ml dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times, wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure get product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate;
Perhaps get 0.21g zinc-copper mixture, 0.62g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate is added among 10ml benzene and the 0.5mlDMF, 50 degree N
2Protection adds catalyzer 0.2g and 2,4,5-trifluoro iodobenzene 1.27g or 1.20g 2 down, 4, the 5-trifluorobromobenzene is in 70 degree reaction 15h, adding finishes, and high performance liquid phase is followed the tracks of reaction, ethyl acetate 50ml dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times, wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure get product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate;
5) hydrolysis and amidated
With 1.3g (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate, add methyl alcohol and mass percent 30% lithium hydroxide aqueous solution, after reacting completely, the neutralization extraction, add 1.0gDCC after dry the concentrating, 1.2g 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 0.5g triethylamine slowly rise to and continue the reaction after-filtration that finishes after the room temperature and remove the N of generation, a N ' dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again to revolve less to steam to remove after residue dissolves with small amount of acetic acid second vinegar and desolvate, the residue column chromatography for separation gets white foam shape solid 1.5g;
6) deprotection base and salify
2g is dissolved in the methylene dichloride through the white foam shape solid that hydrolysis and amidated obtain, and adds the 1ml trifluoroacetic acid, reacts after 3 hours, pour in the frozen water neutralization, extraction into, concentrate the back and add 10ml ethanol, add massfraction 85% phosphate aqueous solution 1.20g again after, temperature rises to 70～74 ℃, add the sitagliptin phosphate crystal seed, at room temperature place 18h, filter crystal, wash with ethanol, 40 ℃ of following vacuum-dryings get white powder solid phosphoric acid sitagliptin hydrate.
Compared with prior art the present invention has following beneficial effect: method of the present invention overcomes the limitation that process is loaded down with trivial details, security is not high, the optics degree is not high, product cost is high in the prior art operation, has the following advantages:
1, starting raw material of the present invention is directly used chiral amino acid, and raw material is easy to get, and production cost is low, production process safety.
2, the present invention requires simple, easy and simple to handle to production unit.
3, synthetic good product quality, yield height, optical purity height.
Description of drawings
Fig. 1 is the hydrogen spectrogram of (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate
Fig. 2 is (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate hydrogen spectrogram
Embodiment
Below by specific embodiment explanation the present invention, but the present invention not merely is defined in these embodiment.
Embodiment 1
1) amido protecting
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, methyl alcohol 200ml, cooling Dropwise 5 ml sulfur oxychloride drips stirring at room 5h, and the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid methyl ester hydrochloride 40g;
Magnetic stirring apparatus is being housed, is adding 4-L-aspartic acid methyl ester hydrochloride 20g in the there-necked flask of thermometer, sodium bicarbonate 20g, water-soluble and 1, in the 4-dioxane, molten clear back adding BOC acid anhydrides, stirring is spent the night, and suction filtration, mother liquor add water 2L, regulate pH with hydrochloric acid.Use ethyl acetate extraction then 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing obtain pale yellow oily liquid body N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters 31g;
2) esterification
30g N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters is dissolved in the ethyl acetate, add N-maloyl imines 29g again, agitation and dropping 30g EDCI, be dissolved in the 100ml ethyl acetate, stir suction filtration, the mother liquor washed twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets pale yellow oily liquid body (3S)-N-tertbutyloxycarbonyl-3-amino-4-succimide oxygen base methyl-butyrate 39g;
3) reduction and iodo
Reduction: get the 1.4g sodium borohydride and be dissolved in 100mlTHF, be added drop-wise among 20g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate and the 50ml THF, there are a large amount of bubbles to generate, temperature is increased to 30 ℃, drips to finish the some plate, react completely, ethyl acetate extraction 2 times, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets 5.5g;
Iodo: the 9.8g triphenyl phosphorus is dissolved in the 70ml methylene dichloride, molten clear back adds the 1g imidazoles, adds 2g iodine, and it is 34 Celsius that temperature rises to, behind the reaction 20min, slowly add the above-mentioned pale yellow oily liquid body that obtains of 3.8g, the some plate is followed the tracks of reaction, suction filtration after raw material point disappears, saturated common salt washing 2 times, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate 3.5g;
4) coupling
Get zinc powder 1.48g, 2.5mlDMF, 50 degree N
2Protection adds glycol dibromide 1ml, stirring reaction 20min down, stop heating, 30 degree add trimethylchlorosilane down, react faint heat release, add 1.3g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate and 10mlDMF solution behind the 20min, the point plate is followed the tracks of reaction, raw material point disappears behind the 30min, adds catalyzer bi triphenyl phosphorus Palladous chloride 0.2g, and 30 degree syringe down slowly inject 2,4,5-trifluoro iodobenzene 1.27g, exothermic heat of reaction, adding finishes, high performance liquid phase is followed the tracks of reaction, ethyl acetate 50ml dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times, wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure get product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate;
5) hydrolysis and amidated
With 1.3g (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate, add methyl alcohol and mass percent 30% lithium hydroxide aqueous solution, after reacting completely, the neutralization extraction, add 1.0gDCC after dry the concentrating, (1.2g3-trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 0.5g triethylamine slowly rise to and continue the reaction after-filtration that finishes after the room temperature and remove the N of generation, a N ' dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again to revolve less to steam to remove after residue dissolves with small amount of acetic acid second vinegar and desolvate, the residue column chromatography for separation gets white foam shape solid 1.5g;
6) deprotection base and salify
2g is dissolved in the methylene dichloride through the white foam shape solid that hydrolysis and amidated obtain, and adds the 1ml trifluoroacetic acid, reacts after 3 hours, pour in the frozen water neutralization, extraction into, concentrate the back and add 10ml ethanol, add massfraction 85% phosphate aqueous solution 1.20g again after, temperature rises to 70～74 ℃, add the sitagliptin phosphate crystal seed, at room temperature place 18h, filter crystal, wash with ethanol, 40 ℃ of following vacuum-dryings get white powder solid phosphoric acid sitagliptin hydrate.
Embodiment 2
1) amido protecting
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 22g in the there-necked flask of thermometer, ethanol 250ml, cooling drips the 12ml sulfur oxychloride, drips stirring at room 5h, and the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid carbethoxy hydrochloride 40g;
Magnetic stirring apparatus is being housed, is adding 4-L-aspartic acid carbethoxy hydrochloride 22g in the there-necked flask of thermometer, sodium bicarbonate 28g, water-soluble and 1, in the 4-dioxane, molten clear back adding BOC acid anhydrides, stirring is spent the night, and suction filtration, mother liquor add water 2L, regulate pH with hydrochloric acid.Use ethyl acetate extraction then 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing obtain pale yellow oily liquid body N-tertbutyloxycarbonyl-4-L-aspartic acid ethyl ester 37g;
2) esterification
31g N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters is dissolved in the ethyl acetate, add N-maloyl imines 32g again, agitation and dropping 32g EDCI, be dissolved in the 150ml ethyl acetate, stir suction filtration, the mother liquor washed twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets pale yellow oily liquid body (3S)-N-tertbutyloxycarbonyl-3-amino-4-hydroxy-ethyl butyrate 43g;
3) reduction and iodo
Reduction: get the 1.4g sodium borohydride and be dissolved in 100mlTHF, be added drop-wise among 20g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate and the 50ml THF, there are a large amount of bubbles to generate, temperature is increased to ℃, drips to finish the some plate, react completely, ethyl acetate extraction 2 times, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets 5.5g;
Iodo: the 9.8g triphenyl phosphorus is dissolved in the 70ml methylene dichloride, molten clear back adds the 1g imidazoles, adds 2g iodine, and it is 34 Celsius that temperature rises to, behind the reaction 20min, the above-mentioned 3.5g pale yellow oily liquid body that the dropping reduction obtains and the solution of 20ml methylene dichloride, the some plate is followed the tracks of reaction, raw material point disappearance back suction filtration, saturated common salt washing 2 times, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine ethyl butyrate 3.7g;
4) coupling
Get zinc powder 1.48g, 2.5mlDMF, 50 degree N
2Protection adds glycol dibromide 1ml, stirring reaction 20min down, stop heating, 30 degree add trimethylchlorosilane down, react faint heat release, add 1.3g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine ethyl butyrate and 10mlDMF solution behind the 20min, the point plate is followed the tracks of reaction, raw material point disappears behind the 30min, adds catalyzer palladium chloride 0.2g, and 30 degree syringe down slowly inject 1.20g 2,4, the 5-trifluorobromobenzene, exothermic heat of reaction, adding finishes, high performance liquid phase is followed the tracks of reaction, ethyl acetate 50ml dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times, wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure get product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) ethyl butyrate;
5) hydrolysis and amidated
With 1.4g (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate, add methyl alcohol and mass percent 30% lithium hydroxide aqueous solution, after reacting completely, the neutralization extraction, add 1.3gDCC after dry the concentrating, (1.4g3-trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 0.6g triethylamine slowly rise to and continue the reaction after-filtration that finishes after the room temperature and remove the N of generation, a N ' dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again to revolve less to steam to remove after residue dissolves with small amount of acetic acid second vinegar and desolvate, the residue column chromatography for separation gets white foam shape solid 1.5g;
6) deprotection base and salify
21g is dissolved in the methylene dichloride through the white foam shape solid that hydrolysis and amidated obtain, and adds the 9ml trifluoroacetic acid, reacts after 4 hours, pour in the frozen water neutralization, extraction into, concentrate the back and add 90ml ethanol, add massfraction 85% phosphate aqueous solution 12.0g again after, temperature rises to 70～74 ℃, add the sitagliptin phosphate crystal seed, at room temperature place 18h, filter crystal, wash with ethanol, 40 ℃ of following vacuum-dryings get white powder solid phosphoric acid sitagliptin hydrate.
Embodiment 3
1) amido protecting
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, methyl alcohol 200ml, cooling Dropwise 5 ml sulfur oxychloride drips stirring at room 5h, and the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid methyl ester hydrochloride 40g;
Magnetic stirring apparatus is being housed, is adding 4-L-aspartic acid methyl ester hydrochloride 20g in the there-necked flask of thermometer, sodium bicarbonate 20g, water-soluble and 1, in the 4-dioxane, molten clear back adding BOC acid anhydrides, stirring is spent the night, and suction filtration, mother liquor add water 2L, regulate pH with hydrochloric acid.Use ethyl acetate extraction then 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing obtain pale yellow oily liquid body N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters 31g;
2) esterification
30g N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters is dissolved in the ethyl acetate, add N-maloyl imines 29g again, agitation and dropping 30g EDCI, be dissolved in the 100ml ethyl acetate, stir suction filtration, the mother liquor washed twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets pale yellow oily liquid body (3S)-N-tertbutyloxycarbonyl-3-amino-4-succimide oxygen base methyl-butyrate 39g;
3) reduction and iodo
Reduction: get the 1.4g sodium borohydride and be dissolved in 100mlTHF, be added drop-wise among 20g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate and the 50ml THF, there are a large amount of bubbles to generate, temperature is increased to 30 ℃, drips to finish the some plate, react completely, ethyl acetate extraction 2 times, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets 5.5g;
Iodo: the 9.8g triphenyl phosphorus is dissolved in the 70ml methylene dichloride, molten clear back adds the 1g imidazoles, adds 2g iodine, and it is 34 Celsius that temperature rises to, behind the reaction 20min, slowly add the above-mentioned pale yellow oily liquid body that obtains of 3.8g, the some plate is followed the tracks of reaction, suction filtration after raw material point disappears, saturated common salt washing 2 times, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate 3.5g;
4) coupling
Get 0.21g zinc-copper mixture, 0.62g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate is added among 10ml benzene and the 0.5mlDMF, 50 degree N
2Protection adds palladium catalyst 0.2g and 2,4,5-trifluoro iodobenzene 1.27g down, in 70 degree reaction 15h, adding finishes, and high performance liquid phase is followed the tracks of reaction, ethyl acetate 50ml dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times, wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure get product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate;
5) hydrolysis and amidated
With 1.3g (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate, add methyl alcohol and mass percent 30% lithium hydroxide aqueous solution, after reacting completely, the neutralization extraction, add 1.0gDCC after dry the concentrating, (1.2g3-trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 0.5g triethylamine slowly rise to and continue the reaction after-filtration that finishes after the room temperature and remove the N of generation, a N ' dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again to revolve less to steam to remove after residue dissolves with small amount of acetic acid second vinegar and desolvate, the residue column chromatography for separation gets white foam shape solid 1.5g;
6) deprotection base and salify
2g is dissolved in the methylene dichloride through the white foam shape solid that hydrolysis and amidated obtain, and adds the 1ml trifluoroacetic acid, reacts after 3 hours, pour in the frozen water neutralization, extraction into, concentrate the back and add 10ml ethanol, add massfraction 85% phosphate aqueous solution 1.20g again after, temperature rises to 70～74 ℃, add the sitagliptin phosphate crystal seed, at room temperature place 18h, filter crystal, wash with ethanol, 40 ℃ of following vacuum-dryings get white powder solid phosphoric acid sitagliptin hydrate.
Embodiment 4
1) amido protecting
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, methyl alcohol 200ml, cooling Dropwise 5 ml sulfur oxychloride drips stirring at room 5h, and the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid methyl ester hydrochloride 40g;
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, sodium bicarbonate 20g, water-soluble and 1, in the 4-dioxane, molten clear back adding BOC acid anhydrides, stirring is spent the night, and suction filtration, mother liquor add water 2L, regulate pH with hydrochloric acid.Use ethyl acetate extraction then 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing obtain pale yellow oily liquid body N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters 31g;
2) esterification
30g N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters is dissolved in the ethyl acetate, add N-maloyl imines 29g again, agitation and dropping 30g EDCI, be dissolved in the 100ml ethyl acetate, stir suction filtration, the mother liquor washed twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets pale yellow oily liquid body (3S)-N-tertbutyloxycarbonyl-3-amino-4-hydroxy-methyl-butyrate 39g; The 30g pale yellow oily liquid body that perhaps amido protecting is obtained is dissolved in the methylene dichloride, and cooling adds the 45g isobutyl chlorocarbonate, adds 23gN-maloyl imines again, be stirred to fully, add water washing twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets the pale yellow oily liquid body;
3) reduction and iodo
Reduction: get the 1.4g sodium borohydride and be dissolved in 100mlTHF, be added drop-wise among 20g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate and the 50ml THF, there are a large amount of bubbles to generate, temperature is increased to 30 ℃, drips to finish the some plate, react completely, ethyl acetate extraction 2 times, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets 5.5g;
Iodo: the 9.8g triphenyl phosphorus is dissolved in the 70ml methylene dichloride, molten clear back adds the 1g imidazoles, add 2g iodine, the pale yellow oily liquid body 3.5g that the dropping reduction obtains behind the reaction 20min, the some plate is followed the tracks of reaction, raw material point disappearance back suction filtration, saturated common salt washing 2 times, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate 3.5g;
4) coupling
In exsiccant 20ml ether, add 0.24g magnesium, add 2.3g 2,4 again, 5-trifluorobromobenzene, N
2Protection adds a small amount of iodine down and causes stirring reaction 20min, 50 degree are after 1 hour, add 0.95g dimethyl sulfide cuprous bromide again, stirring at room 1h, cooling adds 3.3g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate, high performance liquid phase is followed the tracks of reaction, after raw material point disappears, and ethyl acetate 50ml dilute reaction solution, suction filtration, mother liquor, saturated common salt water washing 2 times is washed 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate;
5) hydrolysis and amidated
With 1.3g (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate, add methyl alcohol and mass percent 30% lithium hydroxide aqueous solution, after reacting completely, the neutralization extraction, add 1.0gDCC after dry the concentrating, 1.2g 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 0.5g triethylamine slowly rise to and continue the reaction after-filtration that finishes after the room temperature and remove the N of generation, a N ' dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again to revolve less to steam to remove after residue dissolves with small amount of acetic acid second vinegar and desolvate, the residue column chromatography for separation gets white foam shape solid 1.5g;
6) deprotection base and salify
2g is dissolved in the methylene dichloride through the white foam shape solid that hydrolysis and amidated obtain, and adds the 1ml trifluoroacetic acid, reacts after 3 hours, pour in the frozen water neutralization, extraction into, concentrate the back and add 10ml ethanol, add massfraction 85% phosphate aqueous solution 1.20g again after, temperature rises to 70～74 ℃, add the sitagliptin phosphate crystal seed, at room temperature place 18h, filter crystal, wash with ethanol, 40 ℃ of following vacuum-dryings get white powder solid phosphoric acid sitagliptin hydrate.
Claims (10)
1. the novel method of synthetic sitagliptin phosphate and derivative thereof, it is characterized in that being is raw material with the L-aspartic acid, through amido protecting, esterification, reduction, iodo, coupling, hydrolysis and amidated and deprotection base and salify chemical reaction step obtain sitagliptin phosphate chirality salt and hydrate thereof, be raw material at first with the L-aspartic acid, through amido protecting, esterification, reduction and iodo obtain as compound in structural formula I A, compd A obtains Compound C as structural formula II I through linked reaction again with as the compd B of structural formula II, and Compound C is passed through hydrolysis and amidated again, deprotection base and salt-forming reaction prepare the sitagliptin phosphate hydrate; Structural formula I, structural formula II are used for the synthetic of sitagliptin phosphate and intermediate thereof; Compd A, B, C-structure formula are distinguished as follows:
Wherein:
R
1, R
2Be H, amino protecting group tertbutyloxycarbonyl, benzyl, carbobenzoxy or phthaloyl;
R
3For methoxyl group, oxyethyl group, tert.-butoxy, benzyloxy or as the group of structural formula IV;
X is bromine, iodine or its zincon, boric acid;
Y is triflate, methanesulfonates, p-methyl benzenesulfonic acid ester, bromine or iodine or its zincon;
2. the novel method of synthetic sitagliptin phosphate according to claim 1 and derivative thereof is characterized in that described linked reaction is to obtain Compound C by reaction with chemical combination B under catalyst action again after compd A and magnesium or n-Butyl Lithium or the lithium reaction; Perhaps described linked reaction is that reaction obtains Compound C to compd A formation zincon with compd B again.
3. the novel method of synthetic sitagliptin phosphate according to claim 2 and derivative thereof is characterized in that described catalyzer is bi triphenyl phosphorus Palladous chloride, palladium chloride, nickelous chloride, two (dibenzalacetone) palladium, tetra-triphenylphosphine palladium or palladium.
4. the novel method of synthetic sitagliptin phosphate according to claim 1 and derivative thereof, it is characterized in that described amido protecting may further comprise the steps: magnetic stirring apparatus is being housed, add L-aspartic acid 20g in the there-necked flask of thermometer, methyl alcohol 200ml, cooling Dropwise 5 ml sulfur oxychloride, drip stirring at room 5h, the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid methyl ester hydrochloride 40g; Magnetic stirring apparatus is being housed, add L-aspartic acid and sodium bicarbonate in the there-necked flask of thermometer, water-soluble and 1, in the 4-dioxane, molten clear back adds the BOC acid anhydrides, stirring is spent the night, suction filtration, mother liquor adds water, regulates pH with hydrochloric acid, through after extraction, the drying, the concentrating under reduced pressure desolventizing obtains the pale yellow oily liquid body again.
5. the novel method of synthetic sitagliptin phosphate according to claim 1 and derivative thereof; it is characterized in that described esterification may further comprise the steps: the pale yellow oily liquid body that amido protecting is obtained is dissolved in the ethyl acetate; add N-maloyl imines again; agitation and dropping EDCI or DCC; be dissolved in ethyl acetate; stir; suction filtration, mother liquor washed twice, organic phase anhydrous sodium sulfate drying; the concentrating under reduced pressure desolventizing; get the pale yellow oily liquid body, the pale yellow oily liquid body that perhaps amido protecting is obtained is dissolved in the methylene dichloride, and cooling adds isobutyl chlorocarbonate; add N-maloyl imines again; be stirred to fully, add water washing twice, the organic phase anhydrous sodium sulfate drying; the concentrating under reduced pressure desolventizing gets the pale yellow oily liquid body.
6. the novel method of synthetic sitagliptin phosphate according to claim 1 and derivative thereof, it is characterized in that described reduction and iodo or bromo may further comprise the steps: get sodium borohydride and be dissolved in THF, be added drop-wise in pale yellow oily liquid body and THF that esterification obtains, when having a large amount of bubbles to generate, drip and finish, the some plate, react completely, ethyl acetate extraction, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets the pale yellow oily liquid body; Described iodo may further comprise the steps: triphenyl phosphorus is dissolved in methylene dichloride, and molten clear back adds the solution of imidazoles and iodine and 20ml methylene dichloride, and the some plate is followed the tracks of reaction, suction filtration after raw material point disappears, saturated common salt washing, organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid.
7. the novel method of synthetic sitagliptin phosphate according to claim 2 and derivative thereof is characterized in that described linked reaction may further comprise the steps: get zinc powder and DMF, add 1, the 2-ethylene dibromide, stirring reaction 20min stops heating, adds trimethylchlorosilane down at 30 ℃, react faint heat release, add behind the 20min through iodo obtain as compound in structural formula I A and DMF solution, the some plate is followed the tracks of reaction, raw material point disappearance behind the 30min, add catalyzer, 30 ℃ of following syringes slowly inject 2,4,5-trifluoro iodobenzene or 2,4, the 5-trifluorobromobenzene, exothermic heat of reaction, adding finishes, high performance liquid phase is followed the tracks of reaction, raw material point is used the ethyl acetate dilute reaction solution after disappearing, suction filtration, mother liquor saturated common salt water washing and washing, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product; Perhaps described linked reaction may further comprise the steps: get the zinc-copper mixture, will be added to through the compound in structural formula I A that iodo obtains among benzene and the DMF, 50 degree N
2Protection adds catalyzer and 2,4,5-trifluoro iodobenzene or 2 down, 4, the 5-trifluorobromobenzene is in 70 degree reaction 15h, adding finishes, and high performance liquid phase is followed the tracks of reaction, ethyl acetate dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times is washed 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product; Perhaps described linked reaction may further comprise the steps: in exsiccant 20ml ether, add magnesium, add 2,4 again, 5-trifluoro iodobenzene 2.1g or 2.3g2,4,5-trifluorobromobenzene, N
2Protection adds a small amount of iodine down and causes stirring reaction 20min, and 50 degree add the dimethyl sulfide cuprous bromide after 1 hour again; stirring at room 1h, cooling adds the compound in structural formula I A that iodo obtains, and high performance liquid phase is followed the tracks of reaction; after raw material point disappears; ethyl acetate 50ml dilute reaction solution, suction filtration, mother liquor; saturated common salt water washing 2 times; wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product.
8. the novel method of synthetic sitagliptin phosphate according to claim 1 and derivative thereof, it is characterized in that described hydrolysis and amidated may further comprise the steps: will add methyl alcohol and 30% lithium hydroxide aqueous solution through the product that coupling obtains, after reacting completely, the neutralization extraction, add DCC after dry the concentrating, compound 10 and triethylamine, slowly rise to and continue the reaction after-filtration that finishes after the room temperature and remove the N of generation, N '-dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again after residue dissolves with small amount of acetic acid second vinegar to revolve less to steam to remove and desolvate, the residue column chromatography for separation gets white foam shape solid.
9. the novel method of synthetic sitagliptin phosphate according to claim 1 and derivative thereof; it is characterized in that described deprotection base and salify may further comprise the steps: the white foam shape solid that hydrolysis and amidated are obtained is dissolved in the methylene dichloride; add trifluoroacetic acid; react after 3 hours; pour in the frozen water; neutralization, extraction concentrates the back and adds ethanol; after adding massfraction 85% phosphate aqueous solution again; temperature rises to 70～74 ℃, adds the sitagliptin phosphate crystal seed, at room temperature places 18h; filter crystal; wash with ethanol, 40 ℃ of following vacuum-dryings promptly get white powder solid phosphoric acid sitagliptin hydrate.
10. the novel method of synthetic sitagliptin phosphate according to claim 1 and derivative thereof; it is characterized in that described is raw material with the L-aspartic acid; process amido protecting, esterification, reduction, iodo, coupling, hydrolysis and amidated and deprotection base and salify chemical reaction step obtain sitagliptin phosphate chirality salt and hydrate thereof, and it specifically may further comprise the steps:
1) amido protecting
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, methyl alcohol 200ml, cooling Dropwise 5 ml sulfur oxychloride drips stirring at room 5h, and the concentrating under reduced pressure desolventizing obtains solid 4-L-aspartic acid methyl ester hydrochloride 40g;
Magnetic stirring apparatus is being housed, is adding L-aspartic acid 20g in the there-necked flask of thermometer, sodium bicarbonate 20g, water-soluble and 1, in the 4-dioxane, molten clear back adding BOC acid anhydrides, stirring is spent the night, and suction filtration, mother liquor add water 2L, regulate pH with hydrochloric acid.Use ethyl acetate extraction then 3 times, anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing obtain pale yellow oily liquid body N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters 31g;
2) esterification
30g N-tertbutyloxycarbonyl-4-L-aspartic acid methyl esters is dissolved in the ethyl acetate, add N-maloyl imines 29g again, agitation and dropping 30g EDCI, be dissolved in the 100ml ethyl acetate, stir suction filtration, the mother liquor washed twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets pale yellow oily liquid body (3S)-N-tertbutyloxycarbonyl-3-amino-4-hydroxy-methyl-butyrate 39g; The 30g pale yellow oily liquid body that perhaps amido protecting is obtained is dissolved in the methylene dichloride, and cooling adds the 45g isobutyl chlorocarbonate, adds 23gN-maloyl imines again, be stirred to fully, add water washing twice, the organic phase anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets the pale yellow oily liquid body;
3) reduction and iodo
Reduction: get the 1.4g sodium borohydride and be dissolved in 100mlTHF, be added drop-wise among 20g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate and the 50ml THF, there are a large amount of bubbles to generate, temperature is increased to 30 ℃, drips to finish the some plate, react completely, ethyl acetate extraction 2 times, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing gets 5.5g;
Iodo: the 9.8g triphenyl phosphorus is dissolved in the 70ml methylene dichloride, molten clear back adds the 1g imidazoles, add 2g iodine, the pale yellow oily liquid body 3.5g that the dropping reduction obtains behind the reaction 20min, the some plate is followed the tracks of reaction, raw material point disappearance back suction filtration, saturated common salt washing 2 times, the organic layer anhydrous sodium sulfate drying, the pressure reducing and steaming methylene dichloride gets white solid (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate 3.5g;
4) coupling
In exsiccant 20ml ether, add 0.24g magnesium, add 2,4 again, 5-trifluoro iodobenzene 2.1g or 2.3g 2,4,5-trifluorobromobenzene, N
2Protection adds a small amount of iodine down and causes stirring reaction 20min, 50 degree are after 1 hour, add 0.95g dimethyl sulfide cuprous bromide again, stirring at room 1h, cooling adds 3.3g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate, high performance liquid phase is followed the tracks of reaction, after raw material point disappears, and ethyl acetate 50ml dilute reaction solution, suction filtration, mother liquor, saturated common salt water washing 2 times is washed 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure gets product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate;
Perhaps get 0.21g zinc-copper mixture, 0.62g (3S)-N-tertbutyloxycarbonyl-3-amino-4-iodine methyl-butyrate is added among 10ml benzene and the 0.5mlDMF, 50 degree N
2Protection adds catalyzer bi triphenyl phosphorus Palladous chloride 0.2g and 2,4,5-trifluoro iodobenzene 1.27g or 1.20g 2 down, 4, the 5-trifluorobromobenzene is in 70 degree reaction 15h, adding finishes, and high performance liquid phase is followed the tracks of reaction, ethyl acetate 50ml dilute reaction solution after raw material point disappears, suction filtration, mother liquor, saturated common salt water washing 2 times, wash 2 times, anhydrous sodium sulfate drying, concentrating under reduced pressure get product (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate;
5) hydrolysis and amidated
With 1.3g (3R)-N-tertbutyloxycarbonyl-3-amino-4-(2,4, the 5-trifluorophenyl) methyl-butyrate, add methyl alcohol and mass percent 30% lithium hydroxide aqueous solution, after reacting completely, the neutralization extraction, add 1.0gDCC after dry the concentrating, 1.2g 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 0.5g triethylamine slowly rise to and continue the reaction after-filtration that finishes after the room temperature and remove the N of generation, a N ' dicyclohexylurea (DCU), revolve to steam to remove and desolvate, have again to revolve less to steam to remove after residue dissolves with small amount of acetic acid second vinegar and desolvate, the residue column chromatography for separation gets white foam shape solid 1.5g;
6) deprotection base and salify
2g is dissolved in the methylene dichloride through the white foam shape solid that hydrolysis and amidated obtain, and adds the 1ml trifluoroacetic acid, reacts after 3 hours, pour in the frozen water neutralization, extraction into, concentrate the back and add 10ml ethanol, add massfraction 85% phosphate aqueous solution 1.20g again after, temperature rises to 70～74 ℃, add the sitagliptin phosphate crystal seed, at room temperature place 18h, filter crystal, wash with ethanol, 40 ℃ of following vacuum-dryings get white powder solid phosphoric acid sitagliptin hydrate.
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| CN102627648A (en) * | 2012-04-14 | 2012-08-08 | 江苏施美康药业有限公司 | Preparation method of sitagliptin |
| CN103058888A (en) * | 2011-10-21 | 2013-04-24 | 上海朴颐化学科技有限公司 | Preparation method of (R)-3-t-butyloxycarboryl-amino-4-(2, 4, 5-trifluorobenzene) butyric acid |
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